We are interested in characterizing the molecules and the mechanisms that lead to the beneficial effects exerted by calorie restriction, exercise, and small molecules on skeletal muscle metabolism, with a special emphasis on the role of SIRT1 in these processes. Skeletal muscle accounts for more than 80% of insulin-stimulated whole body glucose uptake, thus playing an important role in the pathogenesis of insulin resistance and type II diabetes. Overall, skeletal muscle of patients with type II diabetes has a diminished oxidative capacity and metabolic inflexibility (i.e., the inability of switching from fat oxidation under fasting conditions to carbohydrate oxidation in response to insulin stimulation). Physical exercise triggers a remodeling program in skeletal muscle that involves changes in metabolic programs and structural proteins within the myofibers. Such adaptations are linked increased expression of genes for contractile proteins that are resistant to fatigue (type I slow-twitch oxidative fibers) and genes involved in mitochondrial respiration, and fatty acid oxidation. These modifications in gene expression that improve performance can also protect against obesity and related metabolic disorders (i.e., type II diabetes and metabolic syndrome). Moreover, skeletal muscles rich in type I slow-twitch oxidative fibers are resistant to muscle wasting. In addition to exercise, dietary interventions aimed at reducing calorie intake can also improve skeletal muscle performance (i.e., improved mitochondrial respiration and improved locomotor function). Reduction of caloric intake to 30%-50% below ad libitum levels, or every-other-day feeding of an ad libitum diet, can delay the onset of age- related diseases, improve stress resistance, and retard organismal functional decline. Small molecule agonists of SIRT1 have been shown to recapitulate, with a good approximation, the effects of calorie restriction in delaying age-related organ deterioration, protecting against diet-induced obesity and insulin resistance, and ameliorating skeletal muscle metabolism and performance. In support of the proposed role of SIRT1 in regulating muscle metabolism in vivo, mice treated with the SIRT1 agonist RSV exhibit increased skeletal muscle mitochondrial function and are resistant to the increase in body mass and insulin resistance normally caused by HFD. RSV counteracts these detrimental changes, at least in part, through the activation of SIRT1 and PGC1-alpha and downstream proteins including MCAD, cytocrome C, estrogen-related receptor alpha (ERR-alpha) and PGC1&#8722;alpha itself. While compelling, this evidence should be interpreted with caution as RSV is not a specific activator of SIRT1 and has been found to modulate several other pathways.